Success with chemotherapeutics as anticancer agents has also been hampered by the phenomenon of multiple drug resistance, resistance to a wide range of structurally unrelated cytotoxic anticancer compounds. J. H. Gerlach et al., Cancer Surveys, 5:25-46 (1986). The underlying cause of progressive drug resistance may be due to a small population of drug-resistant cells within the tumor (e.g., mutant cells) at the time of diagnosis. J. H. Goldie and Andrew J. Coldman, Cancer Research, 44:3643-3653 (1984). Treating such a tumor with a single drug first results in a remission, where the tumor shrinks in size as a result of the killing of the predominant drug-sensitive cells. With the drug-sensitive cells gone, the remaining drug-resistant cells continue to multiply and eventually dominate the cell population of the tumor.
Success treating particular cancers is also hampered by the fact that the cancer is well-advanced by the time it is diagnosed. Pancreatic cancer, colon cancer and breast cancer are good examples of the latter. Pancreatic cancer is diagnosed in almost 38,000 people in the U.S. each year, with almost 35,000 dying from the disease. In Europe the numbers are even higher, with over 60,000 diagnosed each year. Surgery is usually not practical for the majority of cases. Radiation is a contested therapy, with some researchers indicating that radiation stimulates the growth, invasion and metastases of pancreatic cancer. Chemotherapeutics, even in combination, provide only modest (weeks to months) improvements in survival. Overall, median survival from diagnosis is around 3 to 6 months; 5-year survival is less than 5%.
In sheer numbers, colon cancer is even a bigger killer. With 655,000 deaths worldwide per year, it is the third most common form of cancer and the second leading cause of cancer-related death in the Western world. When detected late, surgery may be of no use. For example, 20% of patients present with metastatic (stage 1V) colorectal cancer at the time of diagnosis, and only 25% of this group will have isolated liver metastasis that is potentially resectable. Radiation is not routinely used since it can cause radiation enteritis. Chemotherapy is often used post-surgery as adjunct therapy. However, the use of chemotherapeutics is complicated by the fact that colon cancer is often found in the elderly, who do not respond well to aggressive chemotherapy.
Breast cancer is the most common malignancy and the second leading cause of cancer death in women. In over 60% of localized breast cancer cases, histologic evidence of tumor spread to surrounding tissue is found. Patients diagnosed with invasive ductal carcinoma, the most common breast cancer, have a lower 10-year survival rate. About 30% of newly diagnosed breast cancer patients have positive lymph nodes and much poorer outcomes. Chemotherapeutics are typically employed, but acute chemotherapy-induced adverse effects are observed in most women. These include alopecia, myelosuppression, nausea, stomatitis, vomiting, neuropathy, and myalgia. Later-onset effects often include weight gain, fatigue, musculoskeletal pain, and cognitive dysfunction, especially memory loss, decreased language skills and concentration. Breast cancer chemotherapy toxicities can have severe consequences, including cardiomyopathy or secondary acute leukemia.
What is needed are better compounds and methods for treating cancer, including advanced cancer such as pancreatic cancer, colon cancer and breast cancer.